Mood disorders represent a class of devastating illnesses that have profound impact upon individuals, families, communities, employers, and health care systems. While many medications and therapies exist for the treatment of these illnesses, our understanding of the biological processes disrupted in mood disorders is limited. However, recent advances in genomic technologies have provided new insights into the underlying genetic alterations and gene expression changes present in these illnesses. These and other studies have identified alterations of growth factors and/or growth factor signaling, molecules and processes known to influence many neuronal functions (synaptogenesis, neurogenesis), that may contribute to mood disorders as well as the actions of antidepressants. During the past few years, it has become apparent that numerous small (~22nt) RNAs known as microRNAs (miRNAs) are present in the developing and adult brain. miRNAs function as sequence-specific post-transcriptional regulators of gene expression, by reducing target mRNA levels and/or inhibiting translation. Although only recently identified, miRNA genes are likely to represent more than 1% of all human genes, and it appears that perhaps 20% of all genes are targets of miRNA regulation. Yet, little is known about miRNA expression patterns in the adult brain, or whether changes in miRNA expression occur in human diseases. Recent data (Schratt et al.) has shown a link between miRNA function, neuronal spine development and the action of a specific growth factor, brain derived neurotrophic factor (BDNF), suggesting that miRNAs influence neuronal functions altered in mood disorders. The goals of this application are to (1) determine and characterize miRNA expression patterns in human postmortem brain samples obtained from unipolar and control patients using deep sequencing technologies and (2) characterized the spatial patterns of selected miRNAs in these same patient groups using RNA-probe based in situ hybridization methods developed in our laboratories. These approaches will permit us to define as well as quantify the known and novel microRNA content in these brain regions and how they vary by disease state. We are uniquely positioned to identify miRNAs that are regulated by disease as well as define the spatial patterns of this altered miRNA regulation in human postmortem brain with the intent to more fully understand this miRNA regulation in the brain and in mood disorders. PUBLIC HEALTH RELEVANCE: Our project evaluates small but novel genetic elements called microRNAs (miRNAs) that are thought to have broad influences on the types or amounts of proteins cells produce. Given that we and others have found these miRNAs in adult brain tissue, it prompts questions concerning the biological roles of these genetic elements in the brain and whether miRNAs might play a role(s) in diseases of the brain (e.g. psychiatric disease). Our application seeks to determine if the levels of these miRNAs vary by psychiatric disease state by measuring them using novel deep sequencing methods in human postmortem brain tissues isolated from major depressive disorder and control patient samples.